Method and apparatus for minimizing post-infarct ventricular remodeling

ABSTRACT

A cardiac rhythm management device for in which pre-excitation pacing is applied to one or more sites in proximity to an infarcted region of the ventricular myocardium. Such pacing servers to either prevent or minimize post-infarct remodeling.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.10/005,184, filed on Dec. 5, 2001, the specification of which isincorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to cardiac rhythm management devices such aspacemakers and other implantable devices.

BACKGROUND

A myocardial infarction is the irreversible damage done to a segment ofheart muscle by ischemia, where the myocardium is deprived of adequateoxygen and metabolite removal due to an interruption in blood supply. Itis usually due to a sudden thrombotic occlusion of a coronary artery,commonly called a heart attack. If the coronary artery becomescompletely occluded and there is poor collateral blood flow to theaffected area, a transmural or full-wall thickness infarct can result inwhich much of the contractile function of the area is lost. Over aperiod of one to two months, the necrotic tissue heals, leaving a scar.The most extreme example of this is a ventricular aneurysm where all ofthe muscle fibers in the area are destroyed and replaced by fibrous scartissue.

Even if the ventricular dysfunction as a result of the infarct is notimmediately life-threatening, a common sequela of a transmuralmyocardial infarction in the left ventricle is heart failure broughtabout by ventricular remodeling. Heart failure refers to a conditionwhere cardiac output falls below a level adequate to meet the metabolicneeds of the body which, if uncompensated, leads to rapid death. Onephysiological compensatory mechanism that acts to increase cardiacoutput is the increased diastolic filling pressure of the ventricles asan increased volume of blood is left in the lungs and venous system.This increases the preload, which is the degree to which the ventriclesare stretched by the volume of blood in the ventricles at the end ofdiastole. An increase in preload causes an increase in stroke volumeduring systole, a phenomena known as the Frank-Starling principle.

Left ventricular remodeling is a physiological process in response tothe hemodynamic effects of the infarct that causes changes in the shapeand size of the left ventricle. Remodeling is initiated in response to aredistribution of cardiac stress and strain caused by the impairment ofcontractile function in the infarcted area as well as in nearby and/orinterspersed viable myocardial tissue with lessened contractility due tothe infarct. FIG. 1 illustrates three stages of the remodeling processfollowing a transmural infarction in the apical region of the leftventricle. Stage A is the acute phase which lasts only for a few hours.The infarcted area labeled INF at this stage includes tissue undergoingischemic necrosis and is surrounded by normal myocardium labeled NML.Until scar tissue forms, the infarcted area is particularly vulnerableto the distending forces within the ventricle and undergoes expansionover a period of hours to days as shown at stage B. Over the next fewdays and months after scar tissue has formed, global remodeling andchamber enlargement occur as shown at stage C due to complex alterationsin the architecture of the left ventricle involving both infarcted andnon-infarcted areas. Remodeling is thought to be the result of a complexinterplay of hemodynamic, neural, and hormonal factors.

The ventricular dilation resulting from the increased preload causesincreased ventricular wall stress at a given systolic pressure inaccordance with Laplace's law. Along with the increased pressure-volumework done by the ventricle, this acts as a stimulus for compensatoryhypertrophy of the ventricular myocardium. Hypertrophy can increasesystolic pressures but, if the hypertrophy is not sufficient to meet theincreased wall stress, further and progressive dilation results. Thisnon-compensatory dilation causes wall thinning and further impairment inleft ventricular function. It also has been shown that the sustainedstresses causing hypertrophy may induce apoptosis (i.e., programmed celldeath) of cardiac muscle cells. Thus, although ventricular dilation andhypertrophy may at first be compensatory and increase cardiac output,the process ultimately results in further deterioration and dysfunction.It has been found that the extent of left ventricular remodeling in thelate period after an infarction, as represented by measurements ofend-systolic and end-diastolic left ventricular volumes, is an even morepowerful predictor of subsequent mortality than the extent of coronaryartery disease. Preventing or minimizing such post-infarct remodeling isthe primary concern of the present invention.

SUMMARY

The present invention relates to a method and apparatus for minimizingthe ventricular remodeling that normally occurs after a myocardialinfarction using pacing therapy. The part of the myocardium that is mostvulnerable to the post-infarct remodeling process is the infarct region,which is an area that includes sites in and around the infarct where themyocardial fibers are still intact but contractile function is impaired.The infarct region is thus the area most likely to undergo theprogressive non-compensatory dilation described above with wall thinningand further impairment of function. By pacing sites in proximity to theinfarct with appropriately timed pacing pulses, the infarct region ispre-excited in a manner that lessens the mechanical stress to which itis subjected, thus reducing the stimulus for remodeling. Decreasing thewall stress of the infarct region also lessens the probability of anarrhythmia arising from the region. Another advantage obtained withresynchronizing the ventricular contraction by pre-exciting a weakenedinfarct region is a hemodynamically more efficient contraction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the stages of remodeling after a myocardialinfarction.

FIG. 2 illustrates a pacemaker and an exemplary pacing configuration.

FIG. 3 illustrates a multi-site electrode arrangement.

FIGS. 4A through 4C illustrate examples of patch electrodes formulti-site pacing.

FIG. 5 is a block diagram of an exemplary cardiac rhythm managementdevice for delivering pre-excitation pacing.

DETAILED DESCRIPTION

When a transmural myocardial infarction in the left ventricle occurs,the affected area suffers a loss of contractile fibers that depends uponthe degree of collateral circulation to the area. For example, theinfarction may either leave a non-contractile scar or leave some viablemyocardium interspersed with scar tissue, with the myocardial fibersthat surround the infarcted area suffering a variable amount ofdestruction. In any case, regions in and around the infarct sufferimpaired contractility, and it is this impairment that is responsiblefor the ventricular dysfunction that initiates the remodeling process asdescribed above. Whether the infarction results in a non-contractilescar or a fibrous region with diminished contractility, the viablemyocardium in proximity to the infarct are the regions of the ventriclethat are least able to respond to the increased stresses brought aboutby ventricular dysfunction in a physiologically appropriate manner.These regions are thus the parts of the ventricle that are mostvulnerable to the post-infarct remodeling process. If a way could befound to subject the regions in proximity the infarct to lessenedmechanical stress without unduly compromising ventricular systolicfunction, the undesirable remodeling of the region could be prevented orminimized.

The degree to which a heart muscle fiber is stretched before itcontracts is termed the preload, while the degree of tension or stresson a heart muscle fiber as it contracts is termed the afterload. Themaximum tension and velocity of shortening of a muscle fiber increaseswith increasing preload, and the increase in contractile response of theheart with increasing preload is known as the Frank-Starling principle.When a myocardial region contracts late relative to other regions, thecontraction of those other regions stretches the later contractingregion and increases its preloading, thus causing an increase in thecontractile force generated by the region. Conversely, a myocardialregion that contracts earlier relative to other regions experiencesdecreased preloading and generates less contractile force. Becausepressure within the ventricles rises rapidly from a diastolic to asystolic value as blood is pumped out into the aorta and pulmonaryarteries, the parts of the ventricles that contract earlier duringsystole do so against a lower afterload than do parts of the ventriclescontracting later. Thus, if a ventricular region can be made to contractearlier than parts of the ventricle, it will be subjected to both adecreased preload and afterload which decreases the mechanical stressexperienced by the region relative to other regions. The region willalso do less work thus lessening its metabolic demands and the degree ofany ischemia that may be present.

In accordance with the present invention, electrostimulatory pacingpulses are delivered to one or more sites in or around the infarct in amanner that pre-excites those sites relative to the rest of theventricle. (As the term is used herein, a pacing pulse is any electricalstimulation of the heart of sufficient energy to initiate a propagatingdepolarization, whether or not intended to enforce a particular heartrate.) In a normal heartbeat, the specialized His-Purkinje conductionnetwork of the heart rapidly conducts excitatory impulses from thesino-atrial node to the atrio-ventricular node, and thence to theventricular myocardium to result in a coordinated contraction of bothventricles. Artificial pacing with an electrode fixed into an area ofthe myocardium does not take advantage of the heart's normal specializedconduction system for conducting excitation throughout the ventriclesbecause the specialized conduction system can only be entered byimpulses emanating from the atrio-ventricular node. Thus the spread ofexcitation from a ventricular pacing site must proceed only via the muchslower conducting ventricular muscle fibers, resulting in the part ofthe ventricular myocardium stimulated by the pacing electrodecontracting well before parts of the ventricle located more distally tothe electrode. This pre-excitation of a paced site relative to othersites can be used to deliberately change the distribution of wall stressexperienced by the ventricle during the cardiac pumping cycle.Pre-excitation of the infarct region relative to other regions unloadsthe infarct region from mechanical stress by decreasing its afterloadand preload, thus preventing or minimizing the remodeling that wouldotherwise occur. In addition, because the contractility of the infarctregion is impaired, pre-excitation of the region results in aresynchronized ventricular contraction that is hemodynamically moreeffective. This is beneficial in reducing the stimulus for remodelingand reducing the incidence of angina due to coronary insufficiency.Decreasing the wall stress of the infarct region also lessens its oxygenrequirements and lessens the probability of an arrhythmia arising in theregion.

Pacing therapy to unload the infarct region may be implemented by pacingthe ventricles at a single site in proximity to the infarct region or bypacing at multiple ventricular sites in such proximity. In the lattercase, the pacing pulses may be delivered to the multiple sitessimultaneously or in a defined pulse output sequence. As describedbelow, the single-site or multiple site pacing may be performed inaccordance with a bradycardia pacing algorithm such as an inhibiteddemand mode or a triggered mode.

In order to pre-excite the infarct region, one or more pacing electrodesmust be placed in proximity to the region. The area of the infarct canbe identified by a number of means, including ultrasonic imaging, PETscans, thallium scans, and MRI perfusion scans. In the case of a leftventricular infarct, epicardial leads can either be placed directly onthe epicardium with a thoracotomy (an open chest surgical operation) ora thorascopic procedure, or leads can be threaded from the upper venoussystem into a cardiac vein via the coronary sinus. (See, e.g., U.S. Pat.No. 5,935,160 issued to Auricchio et al., and assigned to CardiacPacemakers, Inc., which is hereby incorporated by reference.) FIG. 2 isan exemplary depiction of two such leads L1 and L2 that are passed froma pacemaker PM through cardiac veins in the epicardium of the leftventricle so that the pacing electrodes E1 and E2 are disposed adjacentto the infarct region INF. In the case of lead placement by athoracotomy or thorascopic procedure, it is possible to dispose theelectrodes in a manner that more precisely circumscribes or overlies theinfarct region. FIG. 3 shows an example of multiple electrodes E1through E4 placed around the infarct region INF, where the electrodesmay either be connected to the pacemaker by a single lead or separateleads for each electrode. FIG. 4A shows another example of an electrodearrangement where the multiple electrodes E1 through E7 are incorporatedinto a patch P1 so as to surround or overlay the infarct region INF.FIG. 4B shows another example of a patch P2 in which the electrode is asingle continuous conductor C1 that is designed to surround the infarctregion. FIG. 4C shows an exemplary construction of the conductor C1where areas on the outer surface of the conductor are intermittentlycoated with an insulating material IM so as to increase the currentdensity at the uncoated regions when the conductor is energized. Such ahigher current density may be necessary in some cases to excite amyocardial region which has been rendered less excitable by ischemia.

A block diagram of an exemplary pacemaker for delivering pre-excitationpacing therapy to a site or sites in proximity to an infarct asdescribed above is illustrated in FIG. 5. Pacemakers are usuallyimplanted subcutaneously on the patient's chest, and are connected tosensing/pacing electrodes by leads either threaded through the vesselsof the upper venous system to the heart or by leads that penetrate thechest wall. (As the term is used herein, a “pacemaker” should be takento mean any cardiac rhythm management device with a pacing functionalityregardless of any other functions it may perform.) The controller of thepacemaker is made up of a microprocessor 10 communicating with a memory12 via a bidirectional data bus, where the memory 12 typically comprisesa ROM (read-only memory) for program storage and a RAM (random-accessmemory) for data storage. The controller could be implemented by othertypes of logic circuitry (e.g., discrete components or programmablelogic arrays) using a state machine type of design, but amicroprocessor-based system is preferable. The controller is capable ofoperating the pacemaker in a number of programmed modes where aprogrammed mode defines how pacing pulses are output in response tosensed events and expiration of time intervals. A telemetry interface 80is also provided for communicating with an external programmer.

The device illustrated in FIG. 5 has multiple sensing and pacingchannels and is therefore capable of delivering single-site or multiplesite ventricular pacing. The multiple sensing and pacing channels may beconfigured as either atrial or ventricular channels allowing the deviceto deliver such pacing with or without atrial tracking. Shown in FIG. 5is a configuration with one atrial sensing/pacing channel and threeventricular sensing/pacing channels. The atrial sensing/pacing channelcomprises ring electrode 53 a, tip electrode 53 b, sense amplifier 51,pulse generator 52, and an atrial channel interface 50 whichcommunicates bidirectionally with a port of microprocessor 10. The threeventricular sensing/pacing channels that include ring electrodes 23 a,33 a, and 43 a, tip electrodes 23 b, 33 b, and 43 b, sense amplifiers21, 31, and 41, pulse generators 22, 32, and 42, and ventricular channelinterfaces 20, 30, and 40. A pacing channel is made up of the pulsegenerator connected to the electrode while a sensing channel is made upof the sense amplifier connected to the electrode. The channelinterfaces include analog-to-digital converters for digitizing sensingsignal inputs from the sensing amplifiers, registers that can be writtento for adjusting the gain and threshold values of the sensingamplifiers, and registers for controlling the output of pacing pulsesand/or changing the pacing pulse amplitude. In certain patients, pacingof sites in proximity to an infarct or within ischemic regions may beless excitable than normal and require an increased pacing energy inorder to achieve capture (i.e., initiating of a propagating actionpotential). For each channel, the same electrode pair can be used forboth sensing and pacing. In this embodiment, bipolar leads that includetwo electrodes are used for outputting a pacing pulse and/or sensingintrinsic activity. Other embodiments may employ a single electrode forsensing and pacing in each channel, known as a unipolar lead. A MOSswitching network 70 controlled by the microprocessor is used to switchthe electrodes from the input of a sense amplifier to the output of apulse generator.

The controller 10 controls the overall operation of the device inaccordance with programmed instructions stored in memory. The controller10 interprets electrogram signals from the sensing channels and controlsthe delivery of paces in accordance with a pacing mode. The sensingcircuitry of the pacemaker generates atrial and ventricular electrogramsignals from the voltages sensed by the electrodes of a particularchannel. When an electrogram signal in an atrial or sensing channelexceeds a specified threshold, the controller detects an atrial orventricular sense, respectively, which pacing algorithms may employ totrigger or inhibit pacing.

Pre-excitation pacing of one or more ventricular sites in proximity toan infarct may be delivered with a bradycardia pacing mode, which refersto a pacing algorithm that enforces a certain minimum heart rate.Pacemakers can enforce a minimum heart rate either asynchronously orsynchronously. In asynchronous pacing, the heart is paced at a fixedrate irrespective of intrinsic cardiac activity. Because of the risk ofinducing an arrhythmia with asynchronous pacing, most pacemakers fortreating bradycardia are programmed to operate synchronously in aso-called demand mode where sensed cardiac events occurring within adefined interval either trigger or inhibit a pacing pulse. Inhibiteddemand pacing modes utilize escape intervals to control pacing inaccordance with sensed intrinsic activity. In an inhibited demandventricular pacing mode, the ventricle is paced during a cardiac cycleonly after expiration of a defined escape interval during which nointrinsic beat by the chamber is detected. For example, a ventricularescape interval can be defined between ventricular events so as to berestarted with each ventricular sense or pace. The inverse of thisescape interval is the minimum rate at which the pacemaker will allowthe ventricles to beat, sometimes referred to as the lower rate limit(LRL). In an atrial tracking pacing mode, another ventricular escapeinterval is defined between atrial and ventricular events, referred toas the atrio-ventricular interval (AVI). The atrio-ventricular intervalis triggered by an atrial sense and stopped by a ventricular sense orpace. A ventricular pace is delivered upon expiration of theatrio-ventricular interval if no ventricular sense occurs before theexpiration. Because it is only paced beats that pre-excite the infarctregion, it may be desirable in certain patients to decrease the AVI tobe below the intrinsic PR interval (i.e., the normal time for anintrinsic ventricular beat to occur after an atrial sense) or increasethe LRL to be slightly above the patient's normal resting heart rate.

In the case where the pre-excitation pacing of the ventricle isdelivered at multiple sites, the sites may be paced simultaneously or inaccordance with a particular pulse output sequence that specifies theorder in which the sites are to be paced during a single beat. Asaforesaid, one of the benefits of pre-excitation pacing of the infarctregion is resynchronization of the contraction that results inhemodynamic improvement. In some patients, such resynchronization may bemore successful if multiple ventricular sites are paced in a specifiedsequence such that certain of the pacing sites are pre-excited earlierthan others during a single beat.

It was noted above that another benefit of pre-exciting ventriculartissue during systole is a reduction in its oxygen requirements, thuspreventing or alleviating ischemia in the infarct region. Pre-excitationpacing as described above may also be employed to unload ischemicregions in either the atria or ventricles that are not associated withan infarct, which may act to prevent the development of angina in thepatient or a subsequent infarct. Ischemic regions, whether or notassociated with an infarct, can be identified with an angiogram,thallium scan or an MRI perfusion scan, and sites within ischemicregions so identified can be selected as pacing sites.

In a further refinement, pre-excitation pacing therapy may be started,stopped, or modified based upon sensor measurements. For example, thepacemaker could measure the impedance between pairs of electrodes todetect wall motion or changes in wall thickness during the cardiaccycle. Separate pairs of electrodes can be used to produce impedancesignals from both a paced region and a non-ischemic region, such as theright ventricle if the paced and ischemic region is in the leftventricle. Ischemia in the paced region can then be monitored bycomparing the timing of the contraction in the paced region with thetiming of the non-ischemic region. If the contractions in the pacedregion is delayed or significantly prolonged, an increase in ischemiacan be surmised, and pre-excitation pacing to the area can either bestarted or increased. Conversely, if a decrease in ischemia is detected,pre-excitation pacing may either be stopped or reduced. Modifications tothe pacing therapy can also be made in accordance with detected changesin the wall thickness of the paced region. In another embodiment, anaccelerometer or microphone on the pacing lead or in the device packagemay be used to sense the acoustic energy generated by the heart during acardiac cycle. Changes in the amplitude or morphology of the acousticenergy signal may then be used to infer changes in the wall motion andthe efficiency of contraction and relaxation. The applied pre-excitationpacing therapy can then be modified based upon this information. (SeeU.S. Pat. No. 6,058,329, hereby incorporated by reference.)

A device for delivering pre-excitation pacing therapy as described abovemay also have other functionality that can be of benefit to patientswith ischemic heart disease, such as cardioversion/defibrillation. Drugdelivery capability incorporated into the device may also be useful.FIG. 5 shows a drug delivery system interfaced to the microprocessorwhich may take various forms. For example, to improve the efficacy ofthe pre-excitation therapy in preventing or minimizing remodeling, itmay be desirable to simultaneously treat the patient with ACE(angiotensin converting enzyme) inhibitors or beta-blockers. It may alsobe useful to deliver biological agents such as growth factors oranti-apoptotic factors directly to the infarct region. Such delivery maybe implemented by infusing the agent through a lumen in a pacing leadthat is disposed near the infarct.

Although the invention has been described in conjunction with theforegoing specific embodiments, many alternatives, variations, andmodifications will be apparent to those of ordinary skill in the art.Other such alternatives, variations, and modifications are intended tofall within the scope of the following appended claims.

1. A method for minimizing post-infarct ventricular remodeling,comprising: identifying an infarcted area in a ventricle; deliveringpacing pulses to one or more sites in proximity to the infarcted area;and, wherein the pacing pulses are delivered in a manner thatpre-excites the site or sites in proximity to the infarcted arearelative to other areas of the ventricle.
 2. The method of claim 1wherein the pacing pulses are delivered in accordance with a bradycardiapacing mode.
 3. The method of claim 2 wherein the pacing mode is aninhibited demand ventricular pacing mode.
 4. The method of claim 2wherein the pacing mode is an atrial tracking mode.
 5. The method ofclaim 1 wherein paces are delivered to multiple sites in proximity tothe infarcted area simultaneously.
 6. The method of claim 1 whereinpaces are delivered to multiple sites in proximity to the infarcted areain an order defined by a specified pulse output sequence.
 7. The methodof claim 1 further comprising modifying the delivery of pacing pulses inaccordance with impedance sensor measurements that indicate ventricularwall motion or thickness.
 8. The method of claim 1 wherein the pacingpulse are delivered to multiple sites via a patch having electrodes thatcircumscribe a region in proximity to the infarcted area.
 9. The methodof claim 1 wherein the site or sites to which pacing pulses aredelivered are located in the left ventricle.
 10. The method of claim 1further comprising modifying the delivery of pacing pulses based uponthe sensing of acoustic energy generated by the heart during a cardiaccycle.
 11. The method of claim 9 wherein the site or sites are pacedwith one or more electrodes disposed in a cardiac vein.
 12. A method foralleviating ischemia in a ventricular region, comprising: identifying anischemic region in a ventricle; delivering pacing pulses to one or moresites in proximity to the ischemic region; and, wherein the pacingpulses are delivered in a manner that pre-excites the site or sites inproximity to the ischemic region relative to other areas of theventricle.
 13. The method of claim 12 further comprising modifying thedelivery of pacing pulses is modified in accordance with impedancesensor measurements that indicate ventricular wall motion or thickness.14. The method of claim 12 further comprising modifying the delivery ofpacing pulses based upon the sensing of acoustic energy generated by theheart during a cardiac cycle.
 15. A cardiac rhythm management device fordelivering pre-excitation pacing therapy to minimize post-infarctventricular remodeling, comprising: one or more sensing channels forsensing intrinsic cardiac activity; a plurality of pacing channels fordelivering pacing pulses; a controller for controlling the delivery ofpacing pulses in accordance with a pacing mode; a patch havingincorporated therein a plurality of pacing electrodes incorporated intothe pacing channels, the electrodes located on the periphery of thepatch so as to circumscribe an infarct region when the patch is placedthereon.
 16. The device of claim 15 further comprising a drug deliverysystem for delivering an agent selected from a group consisting of anACE inhibitor, a beta blocker, a growth factor, and an anti-apoptoticfactor.
 17. The device of claim 15 further comprising an impedancesensor for detecting changes in wall motion and wall thickness in anarea in proximity to the infarct and wherein the controller isprogrammed to modify the delivery of pacing pulses in accordancetherewith.
 18. The device of claim 15 further comprising an acousticsensor for sensing acoustic energy generated by the heart during acardiac cycle and wherein the controller is programmed to modify thedelivery of pacing pulses in accordance therewith.